Endothelial cells (ECs) of arteries are important for the trafficking of nutrients and participate in many physiologic events, such as inflammation and angiogenesis. Atherosclerosis is primarily associated with a series of reactions within the tunica intima and involves monocyte recruitment, macrophage formation, lipid accumulation, extracellular matrix (ECM) production, and smooth muscle cell migration. Compounds with inhibitory effects on vascular inflammation and cell migration would be beneficial for antiatherogenic progression.
Rutaecarpine (RUT) is one of the main bioactive ingredients extracted from the traditional medicine Evodia rutaecarpa and can improve atherosclerosis by preventing monocyte adhesion to the vascular endothelium. RUT reduced the prostaglandin production of lipopolysaccharide (LPS)-activated RAW264.7 macrophages, but did not affect levels of cyclooxygenase (COX)-2 messenger (m)RNA or protein. The vasorelaxant effect of RUT in isolated mesenteric arteries was reported to be associated with Ca2+ flux activity based on in vivo tests on mice. RUT lowered blood pressure through the endothelial Ca2+-nitric oxide (NO)-cGMP pathway to reduce residual muscle tension. The calcitonin gene-related peptide (CGRP), a major neurotransmitter produced in peripheral and central neurons, plays a key role in maintaining endothelial homoeostasis. Decreased plasma CGRP levels cause cardiac susceptibility to ischemia-reperfusion injury, and RUT reverses that decrease by stimulating CGRP production. CGRP counteracts angiotensin (Ang) II-induced endothelial progenitor cell senescence by suppressing reactive oxygen species (ROS) and NADPH oxidase.
Activation of transient receptor potential vanilloid type 1 (TRPV1) in ECs may protect against cardiovascular diseases such as hypertension and stroke. Release of CGRP by activation of vanilloid receptors plays an important role in the vasodilation effects of RUT. NO released by activation of endothelial NO synthase (eNOS) leads to vascular relaxation mediated by CGRP and TRPV1 stimulation. TRPV1-dependent atheroprotection was demonstrated in mice. RUT was reported to be a potential therapeutic agent for arterial thrombosis because of its antiplatelet effect in vivo. Alkaloid compounds also showed anticancer activities by inducing cell cycle arrest or apoptosis in vitro and in vivo. RUT showed high toxicity to lymphoblasts and inhibited ATP-dependent efflux pumps in a blood-brain barrier model with porcine brain capillary ECs, that thus restricts its application in vascular diseases. A variety of structural modifications of natural products were designed and synthesized for better biological applications. RUT derivatives were designed and synthesized to activate TRPV1 for enhanced vasodilator and hypotensive effects. The 14-N atom of RUT is critical for its activity. Bromo-rutaecarpine was designed to broaden the potential for application. However, the bromo-derivative may not be stable enough due to it being more bulky in substitution.
There are still needs for RUT analogs which exhibit very low cytotoxicity, but maintain the anti-inflammatory activity and TRPV1-upregulating effects.